Coxsackieviruses (CVB) are important human pathogens, causing myocarditis, meningitis, and other diseases which may be lethal, especially in neonates. This proposal has five specific aims focused on CVB pathogenesis (Aims 1-3) and immunity (Aims 4, 5). Aim 1. Does CVB preferentially infect proliferating cells in vivo? We have shown, in tissue culture, that the cell cycle exerts a dramatic effect on CVB gene expression & virus production. Is this also true in vivo, in the heart, central nervous system, or immune system? We shall identify proliferating cells in these tissues, and will determine if they are more susceptible to infection. If the heart is injured in vivo, does this alter its susceptibility to subsequent CVB infection? Aim 2. What component of the virus responds to the host cell cycle? Next, we shall study the viral side of the equation. We hypothesize that the internal ribosome entry site may be the viral "response element"; this will be evaluated in tissue culture, and in vivo. Aim 3. What role do the proposed CVB receptors play in tropism & pathogenesis in the heart & CNS? We shall evaluate the expression levels of the receptors. Do they change with age? Following infection / tissue damage, are the receptors upregulated in neighboring cells? Aim 4. How do CD8 [unreadable] T cells contribute to the control of CVB infection ? We have shown that, during CVB infection, CD8 [unreadable] T cells can reduce viral titers, and that this effect does not require perforin. What effector functions are involved in the antiviral effect? Do these effector functions contribute to tissue damage? Aim 5. How does CVB so effectively avoid inducing strong CD8 [unreadable] T cell responses? Most virus infections induce high levels of antiviral CD8 + rl"cells. How does CVB avoid this? Can we rectify the situation?